PROJECT SUMMARY Cytotoxic CD8 T lymphocytes fill a crucial role in adaptive immunity by virtue of their ability to recognize and eliminate pathogen-infected cells and nascent tumors. To accomplish this important function, the T cell antigen receptor (TCR) expressed by CD8 T cells must recognize a pathogen-derived peptide in the context of the major histocompatibility complex (MHC) class I receptor (pMHC). In response to a pathogen infection this TCR-pMHC recognition event by CD8 T cells is crucial in dictating how the ensuing adaptive response manifests. Thus, TCR signaling by nave CD8 T cells is not only important in initiating a protective response but TCR signaling by effector CD8 T cells also underlies its cytotoxic activity for the efficient elimination of infected cells. Accordingly, appropriate TCR-signaling is central for the activation, robust proliferation and function of effector and memory CD8 T cells that ultimately leads to the trafficking of pathogen-specific CD8 T cells to sites of infection and elimination of infected cells via CD8 T cell cytolytic activity. Work from our lab has revealed that an endogenous extracellular lysophospholipid, lysophosphatidic acid (LPA), signals via the LPAR5 G-protein coupled receptor expressed by mature human and mouse T cells and negatively regulates TCR signaling, proliferation and cytotoxic activity. Notably, this lipid and the secreted enzyme responsible for its synthesis are often elevated in inflammatory settings including a number of chronic pathogen infections. Yet, how LPA regulates CD8 T cell biology at these pathophysiological levels or at homeostatic endogenous levels has only been cursorily examined and is not well understood. The experiments described in this proposal are designed to provide a comprehensive understanding of the molecular mechanisms by which the LPAR5 signaling negatively impacts TCR signaling and in vivo CD8 T cell immunity. In addition, given that LPA levels are often increased in chronic infections, we also propose to determine if pathogens that establish chronic infections subvert LPA production to suppress T cell immunity and whether small molecule inhibitors are able to antagonize LPAR5 signaling to promote enhanced immunity. The successful completion of these studies is thus expected to not only extend our current understanding of how CD8 T cells are regulated to provide protective immunity against pathogen infections but also may reveal new avenues of therapeutic intervention that may enhance immunity to persistent infections of global health concern.